In order to target cells HIV must bind 2 receptors. Binding to the receptors not only brings the virus in contact with target cells, it must also trigger the envelope glycoprotein (Env) to mediate fusion between viral and cellular membranes. Our research aims to elucidate the roles of CD4 and chemokine co-receptors in allowing Env to catalyze membrane fusion. Using biochemical and genetic strategies, we have begun to decipher the relationship between viral strain and use of CD4 and/or chemokine receptor in triggering exposure of the fusion peptide, thus initiating membrane fusion. We are focusing on the role of alpha helical regions in gp41 in virus entry because analogous regions in other viruses have proven critical for virus entry, and because 2 different peptides corresponding to these helical regions have proven to be potent inhibitors of HIV entry, presumably by trans-dominantly blocking an Env conformation critical for fusion. We are pursing 3 major approaches; Characterization of inhibition of fusion by alpha-helical gp41 peptides that transdominantly block Env-mediated fusion; Studies of Env chimeric in alpha-helical regions; and Studies of residues critical for fusion as determined by escape mutant viruses resistant to inhibition by peptide. Our studies indicate that different Envs may use the receptors differently for entry and that the alpha-helical regions are critical to virus entry.